Fat Mass And Obesity-associated Risk Research Articles

FTO rs9939609: T>A Variant and Physical Inactivity as Important Risk Factors for Class III Obesity: A Cross-Sectional Study.

The prevalence of obesity has been increasing worldwide. It has been reported that physiological and environmental factors such as diet, culture, physical activity, and genetics are the principal factors related to obesity. The fat mass and obesity-associated (FTO) gen variant (rs9939609: T>A) has been associated with class III obesity. The A variant has been correlated with anthropometric and metabolic alterations. Therefore, the purpose of this study was to analyze the association of the FTO rs9939609: T>A variant and environmental factors with clinical, anthropometric, and biochemical variables in subjects with class III obesity. The A variant frequency was higher in the class III obesity group compared with the normal weight group (44% vs. 25%, p < 0.001). Subjects with the AA genotype had a higher body mass index (BMI) than those with the AT genotype (35.46 kg/m2 (31-39.8) vs. 26.91 kg/m2 (23.7-30), p = 0.005). Women with the AA genotype showed higher waist circumferences than the AT group (101.07 cm (90.9-111.1) vs. 85.45 cm (77-93.8) p = 0.047). The FTO A variant increases the risk by 3.54 times and physical inactivity increases the risk by 6.37 times for class III obesity. Our results suggest that among the studied variables, those most related to class III obesity were the FTO risk genotype (A allele) and physical inactivity.

Interaction Effects of FTO and MC4R Polymorphisms on Total Body Weight Loss, Post-Surgery Weight, and Post-Body Mass Index after Bariatric Surgery.

Bariatric surgery (BS) is considered the most effective intervention for patients with severe obesity and is used to maintain long-term weight loss and glycemic control. The aim of this study was to analyze the effects of genotypes and haplotypes of the fat mass and obesity-associated (FTO) and melanocortin 4 receptor (MC4R) genes on total body weight loss (TBWL), post-surgery weight, and post-BMI after bariatric surgery. We retrospectively selected 101 patients from Bajio High Specialty Regional Hospital, León Guanajuato, México, who underwent Roux-en-Y gastric bypass (RYGB) to determine their body mass index (BMI), blood pressure, biochemical characteristics, and comorbidities. Post-surgery, patients were referred for registered anthropometry and blood pressure. Glucose, lipid and hepatic profiles, and insulin, leptin, and ghrelin levels were measured, and rs9939609, rs9930506, and rs1421085 FTO and rs17782313 MC4R polymorphisms were genotyped. Six (4-8) years after BS, post-surgery weight was greater in carriers of the rs9939609 and rs1421085 risk genotypes. TBWL was lower for the rs9930506 and rs1421085 risk genotypes. Insulin and HOMA-IR were greater in patients with the three FTO polymorphisms. There were significant interaction effects of the rs9930506 and rs1421085 FTO risk genotypes on weight and BMI in response to BS. No association was found with the MC4R polymorphism. The genotypes and haplotypes of the FTO gene influence post-surgery weight, TBWL, insulin levels, and HOMA-IR.

Association Between Adipose Tissue Proton Density Fat Fraction, Resting Metabolic Rate and FTO Genotype in Humans.

BackgroundThe difference of proton density fat fraction (PDFF) between supraclavicular and gluteal adipose tissue might indicate the presence of brown adipose tissue (BAT). Aim of this cross-sectional study was to investigate the association between PDFF over the supraclavicular fat region as a proxy of BAT proportion and resting metabolic rate (RMR). In addition, the association between the single nucleotide polymorphism (SNP) rs1421085 at the fat mass and obesity associated (FTO) gene locus and both PDFF and RMR was investigated.MethodsAnthropometric, clinical, and lifestyle data from 92 healthy adults (66.3% females, mean age: 36.2 ± 13.0 years, mean body mass index: 24.9 ± 5.4 kg/m2) were included in the analysis. The RMR was measured by indirect calorimetry. The magnetic resonance imaging (MRI) was used for the measurement of visceral and subcutaneous adipose tissue (VAT, SAT) volumes and for the measurement of adipose tissue PDFF.ResultsMean RMR of the whole group was 1 474.8 ± 242.2 kcal. Genotype data was available for 90 participants. After adjustment for age, sex, weight change and fat-free mass (FFM), no association was found between supraclavicular PDFF (p = 0.346) and gluteal PDFF (p = 0.252), respectively, and RMR, whereas statistically significant evidence for a negative association between delta PDFF (difference between gluteal PDFF and supraclavicular PDFF) and RMR (p = 0.027) was obtained. No statistically significant evidence was observed for per FTO risk allele change in RMR, gluteal and supraclavicular PDFF maps or volumes of VAT and SAT.ConclusionsSupraclavicular PDFF as a surrogate marker of BAT presence is not a determinant of RMR under basal conditions. In the present study, the FTO rs1421085 variant is not associated with either RMR or PDFF. Further studies are needed to elucidate the effect of BAT on RMR.

Genetic variants in the fat mass and obesity-associated (FTO) gene confer risk for extreme obesity and modulate adiposity in a Brazilian population.

Obesity is a major public health problem worldwide. It has a complex etiology, influenced by environmental and genetic factors. FTO has been recognized as an important genetic factor for obesity development. This study evaluated the contribution of FTO polymorphisms (rs9939609 and rs17817449) for extreme obesity in terms of the period of obesity onset, anthropometric, and biochemical parameters. The haplotype and the combined effects of FTO risk alleles on obesity susceptibility were evaluated. We investigated 169 normal-weight subjects (body mass index, BMI: 22.8 [21.0; 24.0] kg/m2) and 123 extremely obese individuals (BMI: 47.6 [44.1; 53.1] kg/m2). Genotyping was performed by real time PCR. Our results showed a strong association between FTO variants and extreme obesity. Carriers of the AT haplotype had an increased risk for extreme obesity. Gene scores suggested that the risk of developing extreme obesity was increased 1.37-fold per risk allele added. Both polymorphisms also influenced BMI and body weight. Additionally, rs17817449 influenced triglyceride levels. No effect of FTO variants on the period of obesity onset was found. In conclusion, the FTO polymorphisms showed a strong association with development of extreme phenotype of obesity and adiposity modulation in a Brazilian population.

Fat mass and obesity-associated (FTO) rs9939609 polymorphism modifies the relationship between body mass index and affective symptoms through the life course: a prospective birth cohort study

Although bi-directional relationships between high body mass index (BMI) and affective symptoms have been found, no study has investigated the relationships across the life course. There has also been little exploration of whether the fat mass and obesity-associated (FTO) rs9939609 single-nucleotide polymorphism (SNP) is associated with affective symptoms and/or modifies the relationship between BMI and affective symptoms. In the MRC National Survey of Health and Development (NSHD), 4556 participants had at least one measure of BMI and affective symptoms between ages 11 and 60–64 years. A structural equation modelling framework was used with the BMI trajectory fitted as latent variables representing BMI at 11, and adolescent (11–20 years), early adulthood (20–36 years) and midlife (36–53 years) change in BMI. Higher levels of adolescent emotional problems were associated with greater increases in adult BMI and greater increases in early adulthood BMI were associated with higher subsequent levels of affective symptoms in women. The rs9939609 risk variant (A allele) from 2469 participants with DNA genotyping at age 53 years showed mostly protective effect modification of these relationship. Increases in adolescent and early adulthood BMI were generally not associated with, or were associated with lower levels, of affective symptoms in the FTO risk homozygote (AA) group, but positive associations were seen in the TT group. These results suggest bi-directional relationships between higher BMI and affective symptoms across the life course in women, and that the relationship could be ameliorated by rs9939609 risk variant.

Disruption of Accumbens and Thalamic White Matter Connectivity Revealed by Diffusion Tensor Tractography in Young Men with Genetic Risk for Obesity.

Background: Neurovascular coupling is associated with white matter (WM) structural integrity, and it is regulated by specific subtypes of dopaminergic receptors. An altered activity of such receptors, highly expressed in reward-related regions, has been reported in carriers of obesity-risk alleles of the fat mass and obesity associated (FTO) gene. Among the reward-related regions, the thalamus and the nucleus accumbens are particularly vulnerable to blood pressure dysregulation due to their peculiar anatomo-vascular characteristics, and have been consistently reported to be altered in early-stage obesity. We have thus hypothesized that a disruption in thalamus and nucleus accumbens WM microstructure, possibly on neurovascular basis, could potentially be a predisposing factor underlying the enhanced risk for obesity in the risk-allele carriers.Methods: We have tested WM integrity in 21 male participants genotyped on the FTO risk single nucleotide polymorphisms (SNP) rs9939609, through a deterministic tractography analysis. Only homozygous participants (9 AA, 12 TT) were included. 11 tracts were selected and categorized as following according to our hypothesis: “risk tracts”, “obesity-associated tracts”, and a control tract (forcpes major). We investigated whether an association existed between genotype, body mass index (BMI) and WM microstructural integrity in the “risk-tracts” (anterior thalamic radiation and accumbofrontal fasciculus) compared to other tracts. Moreover, we explored whether WM diffusivity could be related to specific personality traits in terms of punishment and reward sensitivity, as measure by the BIS/BAS questionnaire.Results: An effect of the genotype and an interaction effect of genotype and BMI were detected on the fractional anisotropy (FA) of the “risk tracts”. Correlations between WM diffusivity parameters and measures of punishment and reward sensitivity were also detected in many WM tracts of both networks.Conclusions: A disruption of the structural connectivity from the nucleus accumbens and the thalamus might occur early in carriers of the FTO AA risk-allele, and possibly act as a predisposing factor to the development of obesity.

The FTO rs9939609 polymorphism is associated with short leukocyte telomere length in nonobese individuals.

The fat mass and obesity-associated (FTO) rs9939609 polymorphism have been associated with the increased metabolic risk and mortality, irrespective of obesity. The mechanism underlying this association is not known. We aimed to evaluate whether the FTO rs9939609 risk variant is independently associated with metabolic risk factors and/or leukocyte telomere length (LTL). We further aimed to investigate whether this relationship is modified by obesity status.A total of 2133 participants were recruited from the Korean Genome and Epidemiology Study. LTL was measured using the real-time quantitative polymerase chain reaction methodology. The FTO rs9939609 polymorphism was genotyped using DNA samples collected at baseline.The proportions of the TT, TA, and AA genotypes were 76.7%, 21.5%, and 1.8%, respectively, and obese subjects comprised 44.5% of the total subjects. Among the 1184 nonobese subjects, body mass index, waist circumference, and visceral fat area were higher in subjects with the FTO risk allele than in noncarriers. In contrast, only high-sensitive C-reactive protein level was associated with the FTO risk allele in the obese subjects. LTL was significantly shorter in carriers of the FTO risk allele compared with noncarriers after controlling for several confounding factors (P < .01). Of particular note, this significant association between the FTO risk allele and LTL appeared only in nonobese subjects (P = .03). Multivariate linear regression analyses identified older age, low high-density lipoprotein cholesterol level, and the presence of the FTO risk allele as independent risk factors affecting LTL. This finding was evident only in nonobese subjects.The FTO rs9939609 polymorphism is an independent risk factor for obesity and also for biological aging in the nonobese population.

Can genetic-based advice help you lose weight? Findings from the Food4Me European randomized controlled trial1–3

Background: There has been limited evidence about whether genotype-tailored advice provides extra benefits in reducing obesity-related traits compared with the benefits of conventional one-size-fits-all advice.Objective: We determined whether the disclosure of information on fat-mass and obesity-associated (FTO) genotype risk had a greater effect on a reduction of obesity-related traits in risk carriers than in nonrisk carriers across different levels of personalized nutrition.Design: A total of 683 participants (women: 51%; age range: 18–73 y) from the Food4Me randomized controlled trial were included in this analysis. Participants were randomly assigned to 4 intervention arms as follows: level 0, control group; level 1, dietary group; level 2, phenotype group; and level 3, genetic group. FTO (single nucleotide polymorphism rs9939609) was genotyped at baseline in all participants, but only subjects who were randomly assigned to level 3 were informed about their genotypes. Level 3 participants were stratified into risk carriers (AA/AT) and nonrisk carriers (TT) of the FTO gene for analyses. Height, weight, and waist circumference (WC) were self-measured and reported at baseline and months 3 and 6.Results: Changes in adiposity markers were greater in participants who were informed that they carried the FTO risk allele (level 3 AT/AA carriers) than in the nonpersonalized group (level 0) but not in the other personalized groups (level 1 and 2). Mean reductions in weight and WC at month 6 were greater for FTO risk carriers than for noncarriers in the level 3 group [−2.28 kg (95% CI: −3.06, −1.48 kg) compared with −1.99 kg (−2.19, −0.19 kg), respectively (P = 0.037); and −4.34 cm (−5.63, −3.08 cm) compared with −1.99 cm (−4.04, −0.05 cm), respectively, (P = 0.048)].Conclusions: There are greater body weight and WC reductions in risk carriers than in nonrisk carriers of the FTO gene. This trial was registered at clinicaltrials.gov as NCT01530139.

Association study of the FTO gene polymorphisms with the risk of pulmonary tuberculosis in a sample of Iranian population.

The aim of the present study was to find out the impact of fat mass and obesity-associated (FTO) gene on risk of pulmonary tuberculosis (PTB) in a sample of Iranian population. This case-control study was carried out on a total of 354 subjects including 185 PTB patients and 169 healthy subjects. Genotyping of FTO rs9939609 and rs8050136 variants was done using polymerase chain reaction-restriction fragment length polymorphism method. FTO rs9939609 variant showed no statistically significant difference in allele and genotype frequencies between PTB patients and controls. The rs8050136 polymorphism marginally increased the risk of PTB in dominant (OR = 1.53, 95% CI = 1.00-2.33, p = 0.055, CA+AA vs. CC) inheritance model tested, where rs8050136 A allele significantly increased the risk of PTB (OR = 1.42, 95% CI = 1.02-1.97, p = 0.045) compared with C allele. The finding of the present study showed an association between FTO rs9939609 variant and risk of PTB. Further studies with larger sample sizes and different ethnicities are necessary to confirm the findings.

Lack of Association of the Fat Mass and Obesity Associated (FTO) Gene rs9939609 Polymorphism with Breast Cancer Risk: a Systematic Review and Meta-Analysis Based on Case - Control Studies

Background:Previously published data on any association of the fat mass and obesity-associated (FTO) gene with breast cancer risk remain inconclusive. Therefore, we conducted the present meta-analysis of links between breast cancer and the FTO rs9939609 polymorphism.Methods:We have conducted a systematic review of the English literature by searching PubMed, Google Scholar and ISI Web of Knowledge databases for studies on associations between the FTO rs9939609 polymorphism and breast cancer risk. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association using fixed- or random-effects model.Results:We included five studies with 1134 cases and 1453 controls. Overall, no significant association between the FTO rs9939609 polymorphism and risk of breast cancer was found. On subgroup analysis by ethnicity, there was still no significant association detected.Conclusions:To our knowledge, this is the first meta-analysis of the FTO rs9939609 polymorphism and risk of breast cancer. However, the present meta-analysis suggested that only there might be a significant association of the CXCL12 rs1801157 polymorphisms with breast cancer risk.

Genetic Correlation between Body Fat Percentage and Cardiorespiratory Fitness Suggests Common Genetic Etiology.

ObjectivesIt has long been discussed whether fitness or fatness is a more important determinant of health status. If the same genetic factors that promote body fat percentage (body fat%) are related to cardiorespiratory fitness (CRF), part of the concurrent associations with health outcomes could reflect a common genetic origin. In this study we aimed to 1) examine genetic correlations between body fat% and CRF; 2) determine whether CRF can be attributed to a genetic risk score (GRS) based on known body fat% increasing loci; and 3) examine whether the fat mass and obesity associated (FTO) locus associates with CRF.MethodsGenetic correlations based on pedigree information were examined in a family based cohort (n = 230 from 55 families). For the genetic association analyses, we examined two Danish population-based cohorts (ntotal = 3206). The body fat% GRS was created by summing the alleles of twelve independent risk variants known to associate with body fat%. We assessed CRF as maximal oxygen uptake expressed in millilitres of oxygen uptake per kg of body mass (VO2max), per kg fat-free mass (VO2maxFFM), or per kg fat mass (VO2maxFM). All analyses were adjusted for age and sex, and when relevant, for body composition.ResultsWe found a significant negative genetic correlation between VO2max and body fat% (ρG = -0.72 (SE ±0.13)). The body fat% GRS associated with decreased VO2max (β = -0.15 mL/kg/min per allele, p = 0.0034, age and sex adjusted). The body fat%-increasing FTO allele was associated with a 0.42 mL/kg/min unit decrease in VO2max per allele (p = 0.0092, age and sex adjusted). Both associations were abolished after additional adjustment for body fat%. The fat% increasing GRS and FTO risk allele were associated with decreased VO2maxFM but not with VO2maxFFM.ConclusionsOur findings suggest a shared genetic etiology between whole body fat% and CRF.

FTO Obesity Risk Variants Are Linked to Adipocyte IRX3 Expression and BMI of Children - Relevance of FTO Variants to Defend Body Weight in Lean Children?

BackgroundGenome-wide association studies have identified variants within the FTO (fat mass and obesity associated) locus as the strongest predictors of obesity amongst all obesity-associated gene loci. Recent evidence suggests that variants in FTO directly affect human adipocyte function through targeting IRX3 and IRX5 and thermogenesis regulation.AimWe addressed the relevance of this proposed FTO-IRX pathway in adipose tissue (AT) of children.ResultsExpression of IRX3 was higher in adipocytes compared to SVF. We found increased adipocyte-specific expression of IRX3 and IRX5 with the presence of the FTO risk haplotype in lean children, whereas it was unaffected by risk variants in obese peers. We further show that IRX3 expression was elevated in isolated adipocytes and AT of lean compared to obese children, particularly in UCP1-negative adipocytes, and inversely correlated with BMI SDS. Independent of BMI, IRX3 expression in adipocytes was significantly related to adipocyte hypertrophy, and subsequent associations with AT inflammation and HOMA-IR in the children.ConclusionOne interpretation of our observation of FTO risk variants linked to IRX3 expression and adipocyte size restricted to lean children, along with the decreased IRX3 expression in obese compared to lean peers, may reflect a defense mechanism for protecting body-weight, which is pertinent for lean children.

Changes in Physical Activity Following a Genetic-Based Internet-Delivered Personalized Intervention: Randomized Controlled Trial (Food4Me).

BackgroundThere is evidence that physical activity (PA) can attenuate the influence of the fat mass- and obesity-associated (FTO) genotype on the risk to develop obesity. However, whether providing personalized information on FTO genotype leads to changes in PA is unknown.ObjectiveThe purpose of this study was to determine if disclosing FTO risk had an impact on change in PA following a 6-month intervention.Methods The single nucleotide polymorphism (SNP) rs9939609 in the FTO gene was genotyped in 1279 participants of the Food4Me study, a four-arm, Web-based randomized controlled trial (RCT) in 7 European countries on the effects of personalized advice on nutrition and PA. PA was measured objectively using a TracmorD accelerometer and was self-reported using the Baecke questionnaire at baseline and 6 months. Differences in baseline PA variables between risk (AA and AT genotypes) and nonrisk (TT genotype) carriers were tested using multiple linear regression. Impact of FTO risk disclosure on PA change at 6 months was assessed among participants with inadequate PA, by including an interaction term in the model: disclosure (yes/no) × FTO risk (yes/no).ResultsAt baseline, data on PA were available for 874 and 405 participants with the risk and nonrisk FTO genotypes, respectively. There were no significant differences in objectively measured or self-reported baseline PA between risk and nonrisk carriers. A total of 807 (72.05%) of the participants out of 1120 in the personalized groups were encouraged to increase PA at baseline. Knowledge of FTO risk had no impact on PA in either risk or nonrisk carriers after the 6-month intervention. Attrition was higher in nonrisk participants for whom genotype was disclosed (P=.01) compared with their at-risk counterparts.ConclusionsNo association between baseline PA and FTO risk genotype was observed. There was no added benefit of disclosing FTO risk on changes in PA in this personalized intervention. Further RCT studies are warranted to confirm whether disclosure of nonrisk genetic test results has adverse effects on engagement in behavior change.Trial RegistrationClinicalTrials.gov NCT01530139; http://clinicaltrials.gov/show/NCT01530139 (Archived by WebCite at: http://www.webcitation.org/6XII1QwHz)

Fat mass- and obesity-associated genotype, dietary intakes and anthropometric measures in European adults: the Food4Me study.

The interplay between the fat mass- and obesity-associated (FTO) gene variants and diet has been implicated in the development of obesity. The aim of the present analysis was to investigate associations between FTO genotype, dietary intakes and anthropometrics among European adults. Participants in the Food4Me randomised controlled trial were genotyped for FTO genotype (rs9939609) and their dietary intakes, and diet quality scores (Healthy Eating Index and PREDIMED-based Mediterranean diet score) were estimated from FFQ. Relationships between FTO genotype, diet and anthropometrics (weight, waist circumference (WC) and BMI) were evaluated at baseline. European adults with the FTO risk genotype had greater WC (AA v. TT: +1·4 cm; P=0·003) and BMI (+0·9 kg/m2; P=0·001) than individuals with no risk alleles. Subjects with the lowest fried food consumption and two copies of the FTO risk variant had on average 1·4 kg/m2 greater BMI (Ptrend=0·028) and 3·1 cm greater WC (Ptrend=0·045) compared with individuals with no copies of the risk allele and with the lowest fried food consumption. However, there was no evidence of interactions between FTO genotype and dietary intakes on BMI and WC, and thus further research is required to confirm or refute these findings.

Commentary: FTO obesity variant circuitry and adipocyte browning in humans.

Commentary: FTO obesity variant circuitry and adipocyte browning in humans.

Differences in body mass index according to fat mass- and obesity-associated (FTO) genotype in Mexican patients with bipolar disorder.

The prevalence of obesity has dramatically increased in many countries and it is particularly high in patients with bipolar disorder (BD). A region in the first intron of the fat mass- and obesity-associated (FTO) gene, encompassing markers rs9939973, rs8050136, and rs9939609, has been consistently associated with obesity and body mass index (BMI) in different populations. We sought to determine whether FTO is associated with BMI and/or obesity in patients with BD. The sample included 129 Mexican Mestizo patients with bipolar I or bipolar II disorder. After obtaining informed consent, participants were evaluated with the Structured Clinical Interview for DSM-IV Axis I Disorders and weight, height, and body measurements were recorded. DNA was extracted from a 5-mL blood sample and real-time polymerase chain reaction was performed. The results were analyzed with Haploview v4.2 and SPSS v21. Differences in mean BMI were explained by rs8050136 and rs9939609 genotypes, especially by comparing non-carriers and carriers of two copies of the risk allele (Tukey's p ≤ 0.019), with a mean difference in BMI as high as 7.81 kg/m(2) . Differences in BMI were also explained by the interaction of the genotype (rs8050136 and/or rs9939609), the use of second-generation antipsychotics, and the use of mood stabilizers (p ≤ 0.41). Obesity was also associated with these two markers when patients with and without obesity were compared. In patients with BD, differences in BMI may be affected by the presence of FTO risk alleles, especially in homozygous individuals for these variants. Besides evaluating the possible metabolic effects of certain antipsychotics or mood stabilizers, it is important to evaluate the role of other factors such as FTO risk alleles.

Associations between FTO genotype and total energy and macronutrient intake in adults: a systematic review and meta-analysis.

Risk variants of fat mass and obesity-associated (FTO) gene have been associated with increased obesity. However, the evidence for associations between FTO genotype and macronutrient intake has not been reviewed systematically. Our aim was to evaluate the potential associations between FTO genotype and intakes of total energy, fat, carbohydrate and protein. We undertook a systematic literature search in OVID MEDLINE, Scopus, EMBASE and Cochrane of associations between macronutrient intake and FTO genotype in adults. Beta coefficients and confidence intervals (CIs) were used for per allele comparisons. Random-effect models assessed the pooled effect sizes. We identified 56 eligible studies reporting on 213,173 adults. For each copy of the FTO risk allele, individuals reported 6.46 kcal day(-1) (95% CI: 10.76, 2.16) lower total energy intake (P = 0.003). Total fat (P = 0.028) and protein (P = 0.006), but not carbohydrate intakes, were higher in those carrying the FTO risk allele. After adjustment for body weight, total energy intakes remained significantly lower in individuals with the FTO risk genotype (P = 0.028). The FTO risk allele is associated with a lower reported total energy intake and with altered patterns of macronutrient intake. Although significant, these differences are small and further research is needed to determine whether the associations are independent of dietary misreporting.

Genetic Relationship Between Depression and Body Mass Index

Introduction Depression and obesity are highly prevalent major public health problems that frequently co-occur. Shared aetiological factors have been found between depression and obesity. The role of the fat mass and obesity associated ( FTO ) gene in body mass index (BMI) and obesity has been confirmed in many independent studies. Recently, we reported the first study implicating FTO in the association between depression and obesity. Objectives We aimed to confirm these findings by investigating the FTO rs9939609 polymorphism in a meta-analysis of 13,701 individuals. Methods The sample consists of 6,902 depressed cases and 6,799 controls from five studies (Radiant, PsyCoLaus, GSK, MARS and NESDA/NTR). Common inclusion criteria were information available on a lifetime DSM-IV diagnosis of major depressive disorder (MDD), BMI and genotype data. Linear regression models for quantitative traits assuming an additive genetic model were performed to test for association and interaction between rs9939609, BMI and depression. Fixed and random-effects meta-analyses were performed. Results Fixed-effects meta-analyses support a significant association between rs9939609 polymorphism and BMI (whole-sample: s=0.07, p=1.29×10 -12 , depressive-cases: s=0.12, p=6.92×10 -12 ). No association was found in controls (s=0.02, p=0.15). Meta-analyses further support a significant interaction between FTO , BMI and depression (fixed-effects: s=0.13, p=3.087×10 -7 ; random-effects: s=0.12, p=0.027), wherein depressed carriers of the risk allele have an additional increase of 2.2% in BMI. Conclusions This meta-analysis demonstrates a significant interaction between FTO , depression and BMI, indicating that depression increases the effect of FTO on BMI. Depression-related alterations in key biological processes may interact with the rs9939609 FTO risk allele to increase obesity risk.

Cohort of birth modifies the association between FTO genotype and BMI

A substantial body of research has explored the relative roles of genetic and environmental factors on phenotype expression in humans. Recent research has also sought to identify gene-environment (or g-by-e) interactions, with mixed success. One potential reason for these mixed results may relate to the fact that genetic effects might be modified by changes in the environment over time. For example, the noted rise of obesity in the United States in the latter part of the 20th century might reflect an interaction between genetic variation and changing environmental conditions that together affect the penetrance of genetic influences. To evaluate this hypothesis, we use longitudinal data from the Framingham Heart Study collected over 30 y from a geographically relatively localized sample to test whether the well-documented association between the rs993609 variant of the FTO (fat mass and obesity associated) gene and body mass index (BMI) varies across birth cohorts, time period, and the lifecycle. Such cohort and period effects integrate many potential environmental factors, and this gene-by-environment analysis examines interactions with both time-varying contemporaneous and historical environmental influences. Using constrained linear age-period-cohort models that include family controls, we find that there is a robust relationship between birth cohort and the genotype-phenotype correlation between the FTO risk allele and BMI, with an observed inflection point for those born after 1942. These results suggest genetic influences on complex traits like obesity can vary over time, presumably because of global environmental changes that modify allelic penetrance.

FTO polymorphisms moderate the association of food reinforcement with energy intake

Food reinforcement (RRVfood) is related to increased energy intake, cross-sectionally related to obesity, and prospectively related to weight gain. The fat mass and obesity-associated (FTO) gene is related to elevated body mass index and increased energy intake. The primary purpose of the current study was to determine whether any of 68 FTO single nucleotide polymorphisms (SNPs) or a FTO risk score moderate the association between food reinforcement and energy or macronutrient intake. Energy and macronutrient intake was measured using a laboratory ad libitum snack food consumption task in 237 adults of varying BMI. Controlling for BMI, the relative reinforcing value of reading (RRVreading) and proportion of African ancestry, RRVfood predicted 14.2% of the variance in energy intake, as well as predicted carbohydrate, fat, protein and sugar intake. In individual analyses, six FTO SNPs (rs12921970, rs9936768, rs12446047, rs7199716, rs8049933 and rs11076022, spanning approximately 251kbp) moderated the relationship between RRVfood and energy intake to predict an additional 4.9–7.4% of variance in energy intake. We created an FTO risk score based on 5 FTO SNPs (rs9939609, rs8050136, rs3751812, rs1421085, and rs1121980) that are related to BMI in multiple studies. The FTO risk score did not increase variance accounted for beyond individual FTO SNPs. rs12921970 and rs12446047 served as moderators of the relationship between RRVfood and carbohydrate, fat, protein, and sugar intake. This study shows for the first time that the relationship between RRVfood and energy intake is moderated by FTO SNPs. Research is needed to understand how these processes interact to predict energy and macronutrient intake.